Pancreatic ductal adenocarcinoma (PDAC) has the highest mortality rate of all major cancers and is the third and soon to be the second leading cause of cancer-related deaths in the United States. The average life expectancy after diagnosis with metastatic disease is just three to six months. There obviously is an urgent and unmet need for novel effective therapeutic approaches, but identifying therapeutic targets that will increase survival rates of PDAC patients remains one of the greatest challenges in current cancer research. Since nearly 100% of pancreatic ductal adenocarcinoma (PDAC) carried mutational activation of KRAS, KRAS is theoretically ideal candidate for PDAC therapeutic intervention. But targeting KRAS directly has been unsuccessful. As a result, there is significant interest in identifying novel downstream effectors of oncogenic KRAS signaling that could be amenable to pharmacologic intervention. PYK2 (proline-rich tyrosine kinase 2) is a non-receptor cytoplasmic tyrosine kinase, which is expressed at a very low level in normal pancreas. We found that PYK2 was drastically induced in mouse PanIN (pancreatic intraepithelial neoplasia, non-invasive precursor lesions of PDAC) and human PDAC tissues and that PYK2 elevation required KARS and occurred at the transcriptional level. Functionally, our results showed that whole-body deletion of PYK2, even heterozygous deletion, remarkably suppressed PanIN formation in the Pdx1-Cre KRASG12D mouse model. Further, we found that shRNA knockdown of PYK2 abrogated tumor growth in a PDAC cell line xenograft model, suggesting that PYK2 is required for PDAC maintenance. Mechanistically, our data revealed that PYK2 regulates two cancer-related pathways: the Wnt/?- catenin pathway and the NF-?B pathway, both pathways are known important for PDAC genesis and progression. Overall, our preliminary results strongly suggested that PYK2 is a new functionally relevant and druggable target for PDAC. Our central hypothesis of this study is that PYK2 is a novel downstream effector of mutant KRAS signaling essential for PDAC carcinogenesis and maintenance and a new actionable target for treating PDAC. We will test our hypothesis through the following Specific Aims. Aim 1 will validate the role of PYK2 in mutant KRAS-driven PDAC carcinogenesis. Aim 2 will unravel how PYK2 is hard-wired among mutant KRAS-activated signaling networks. Aim 3 will validate PYK2 inhibition as an actionable and effective approach to treating PDAC in preclinical models of PDAC. Successful completion of the aims could prove that PYK2-targeted therapy represents an exciting and potentially promising new approach to treating pancreatic cancer.